NM_024577.4(SH3TC2):c.1969G>A (p.Glu657Lys) AND Charcot-Marie-Tooth disease type 4

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 12, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000206757.8

Allele description [Variation Report for NM_024577.4(SH3TC2):c.1969G>A (p.Glu657Lys)]

NM_024577.4(SH3TC2):c.1969G>A (p.Glu657Lys)

Gene:

SH3TC2:SH3 domain and tetratricopeptide repeats 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q32

Genomic location:

Preferred name:

NM_024577.4(SH3TC2):c.1969G>A (p.Glu657Lys)

HGVS:

NC_000005.10:g.149027763C>T
NG_007947.2:g.40412G>A
NM_024577.4:c.1969G>AMANE SELECT
NP_078853.2:p.Glu657Lys
NP_078853.2:p.Glu657Lys
LRG_269t1:c.1969G>A
LRG_269:g.40412G>A
LRG_269p1:p.Glu657Lys
NC_000005.9:g.148407326C>T
NM_024577.3:c.1969G>A
Q8TF17:p.Glu657Lys

Protein change:

E657K; GLU657LYS

Links:

UniProtKB: Q8TF17#VAR_018269; OMIM: 608206.0007; dbSNP: rs80338925

NCBI 1000 Genomes Browser:

rs80338925

Molecular consequence:

NM_024577.4:c.1969G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Charcot-Marie-Tooth disease type 4
Synonyms:: Charcot-Marie-Tooth, Type 4
Identifiers:: MONDO: MONDO:0018995; MedGen: C4082197

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000260917	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 12, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 14574644, 19272779, 20028792, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000260917

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 12, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy.

Senderek J, Bergmann C, Stendel C, Kirfel J, Verpoorten N, De Jonghe P, Timmerman V, Chrast R, Verheijen MH, Lemke G, Battaloglu E, Parman Y, Erdem S, Tan E, Topaloglu H, Hahn A, Müller-Felber W, Rizzuto N, Fabrizi GM, Stuhrmann M, Rudnik-Schöneborn S, Züchner S, et al.

Am J Hum Genet. 2003 Nov;73(5):1106-19. Epub 2003 Oct 21.

PubMed [citation]

PMID:: 14574644
PMCID:: PMC1180490

The phenotype of Charcot-Marie-Tooth disease type 4C due to SH3TC2 mutations and possible predisposition to an inflammatory neuropathy.

Houlden H, Laura M, Ginsberg L, Jungbluth H, Robb SA, Blake J, Robinson S, King RH, Reilly MM.

Neuromuscul Disord. 2009 Apr;19(4):264-9. doi: 10.1016/j.nmd.2009.01.006. Epub 2009 Mar 9.

PubMed [citation]

PMID:: 19272779

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000260917.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

ClinVar contains an entry for this variant (Variation ID: 21689). This missense change has been observed in individuals with Charcot-Marie-Tooth disease type 4C (PMID: 14574644, 19272779). This variant is present in population databases (rs80338925, gnomAD 0.02%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 657 of the SH3TC2 protein (p.Glu657Lys). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SH3TC2 protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SH3TC2 function (PMID: 20028792).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

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